GFRA4

protein-coding

GDNF family receptor alpha 4

Gene summary

The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for persephin, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for RET-associated diseases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_022139.4

Inheritance

—

ClinVar variants

U:46B:6

Top phenotype

Fetal akinesia deformation sequence 1

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr20:3,659,248-3,663,399

External References & Databases

Ensembl (ENSG00000125861)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GFRA4 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 55

not providedTotal: 1

Fetal akinesia deformation sequence 1Total: 1

Arthrogryposis multiplex congenitaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022139.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar			2
missense			44 clinvar	6 clinvar		50
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	46	6	0	52

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022139.4	RefSeq	NP_071422.1	6	MANE Select
ENST00000290417.7	Ensembl	ENSP00000290417.2	6	MANE Select
NM_145762.3	RefSeq	NP_665705.1	5	Standard
ENST00000319242.8	Ensembl	ENSP00000313423.3	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
Signal Transduction
RAF/MAP kinase cascade
MAPK1/MAPK3 signaling
MAPK family signaling cascades

Biological Process

MAPK cascade
nervous system development
axon guidance
negative regulation of ossification
glial cell-derived neurotrophic factor receptor signaling pathway

Molecular Function

Ras guanyl-nucleotide exchange factor activity
glial cell-derived neurotrophic factor receptor activity

Cellular Component

extracellular space
plasma membrane
external side of plasma membrane
anchored component of membrane
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319242
Coding exons: 5
Length: 4108
Individuals with no LoFs: 113528
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 113530
p: 0.00000881

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.621	87	105	0.829	0.00000643	1760
Missense (PolyPhen)		15	16.174	0.92743		456
Synonymous	-0.568	52	47.0	1.11	0.00000289	689
Loss of Function	0.709	5	7.03	0.712	3.07e-7	105

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00010	0.00010	rare
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for persephin. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor. May be important in C-cell development and, in the postnatal development of the adrenal medulla.;

Recessive Scores

pRec: 0.112

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.255

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium